Pharmaceutical for treatment and / or prevention of cancer

Abstract

To provide a pharmaceutical for treatment and / or prevention of cancer.SOLUTION: The present invention provides a pharmaceutical for treatment and / or prevention of cancer, comprising an antibody or a fragment thereof having immunological reactivity with a CAPRIN-1 protein and an immune checkpoint inhibitor, which are included in combination together or separately.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical for treating and / or preventing cancer using an antibody against CAPRIN-1 protein or a fragment thereof and an immune checkpoint inhibitor. [Background technology]

[0002] Various antibody drugs targeting specific antigen proteins on cancer cells have been applied to cancer treatment as cancer therapeutic agents with few side effects due to their cancer specificity. For example, cytoplasmic-activation and proliferation-associated protein 1 (CAPRIN-1) is expressed on the cell membrane surface of many solid cancers, and antibodies against this CAPRIN-1 protein are known to be promising pharmaceuticals for the treatment and / or prevention of cancer (Patent Document 1).

[0003] In recent clinical trials, the use of multiple anticancer drugs in combination has become standard treatment to enhance the efficacy of cancer treatments. For example, for colorectal cancer, a combination of irinotecan, folinic acid, and fluorouracil is commonly used; for breast cancer, a combination of doxorubicin and cyclophosphamide, or a combination of paclitaxel, trastuzumab, and pertuzumab is commonly used; and for gastric cancer, a combination of multiple anticancer drugs, such as carboplatin and fluorouracil, is commonly used. Cancer treatments containing anti-CAPRIN-1 antibodies as active ingredients have also been shown to have excellent cancer therapeutic effects when used in combination with chemotherapeutic agents (Patent Document 2). However, cancer treatments using combinations of chemotherapeutic agents are not effective against all cancers, and while some may additively enhance therapeutic effects, few significantly synergistically enhance therapeutic effects.

[0004] For patients with malignant melanoma, for example, the median survival time for distant metastases to the skin, lymph nodes, or digestive tract is only 12.5 months (5-year survival rate of only 14%), for lung metastases it is 8.3 months (5-year survival rate of 4%), and for liver, brain, or bone metastases it is 4.4 months (5-year survival rate of 3%), resulting in an extremely poor prognosis. Furthermore, partial resection of metastatic sites is only applicable to patients in good general condition (Non-Patent Document 1).

[0005] Furthermore, in recent years, so-called immune checkpoint inhibitors, which treat cancer by strengthening or complementing the body's immune system against cancer, have been approved or are undergoing clinical trials for many cancers.

[0006] For example, a Phase III trial (CheckMate-067 trial) combining two or more immune checkpoints was conducted, and in the first-line treatment of progressive metastatic melanoma (malignant melanoma) using combination therapy with nivolumab and ipilimumab, the proportion of patients who survived for more than five years (5-year survival rate) was 52% (Non-Patent Document 2).

[0007] In addition, the objective response rate (ORR) in the nivolumab and ipilimumab combination group for untreated advanced / metastatic renal cell carcinoma was 41% in the control group receiving Sutent alone, demonstrating improved efficacy. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] WO2010 / 016526 issue [Patent Document 2] WO2011 / 096535 No. [Non-patent literature]

[0009] [Non-Patent Document 1] J Am Coll Surg,1995,181,193-201 [Non-patent document 2] The New England Journal of Medicine,2019,381,1535-1546 Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide a pharmaceutical agent for treating and / or preventing cancers that specifically express CAPRIN-1 protein on the cell surface. [Means for solving the problem]

[0011] As a result of extensive research, the present inventors have discovered that the combination of an antibody or a fragment thereof against the CAPRIN-1 protein, which has immunological reactivity with cancer cells, with an immune checkpoint inhibitor exerts an extremely strong antitumor effect in cancer patients, particularly in cancer patients with a history of cancer treatment with an immune checkpoint inhibitor, and have thus completed the present invention.

[0012] Specifically, the present invention relates to the following embodiments (1) to (18).

[0013] (1) A pharmaceutical for treating and / or preventing cancer, comprising a combination, either together or separately, of an antibody or a fragment thereof immunologically reactive with CAPRIN-1 protein and an immune checkpoint inhibitor.

[0014] (2) The pharmaceutical according to (1), wherein the immune checkpoint inhibitor is a drug that inhibits the interaction between PD-1 and PD-L1 and / or a drug that inhibits the interaction between CTLA-4 and CD80 or CD86.

[0015] (3) The pharmaceutical according to (1) or (2), wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, and / or an anti-CTLA-1 antibody.

[0016] (4) The pharmaceutical product according to any one of (1) to (3), wherein the immune checkpoint inhibitor is nivolumab.

[0017] (5) The pharmaceutical agent according to any one of (1) to (4), wherein the cancer is a cancer in a cancer patient for whom cancer treatment with a pharmaceutical agent other than cancer treatment with a pharmaceutical agent containing an antibody or a fragment thereof immunologically reactive with CAPRIN-1 protein in combination with an immune checkpoint inhibitor, either together or separately, has been ineffective.

[0018] (6) The pharmaceutical agent according to any one of (1) to (5), wherein the cancer is a cancer in a cancer patient for whom cancer treatment with an immune checkpoint inhibitor has not been effective.

[0019] (7) The pharmaceutical according to any one of (1) to (6), wherein the antibody or fragment thereof is immunologically reactive with a CAPRIN-1 protein having an amino acid sequence represented by any of the even-numbered SEQ ID NOs: 2 to 30, or an amino acid sequence having 80% or more sequence identity with the amino acid sequence.

[0020] (8) The pharmaceutical according to any one of (1) to (7), wherein the antibody or fragment thereof is immunologically reactive with the extracellular domain of CAPRIN-1 protein present on the surface of cancer cells.

[0021] (9) The pharmaceutical according to any one of (1) to (8), wherein the antibody or a fragment thereof is immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having an amino acid sequence represented by any one of SEQ ID NOs: 31 to 35, 296 to 299, 308, and 309, or an amino acid sequence having 80% or more sequence identity with said amino acid sequence.

[0022] (10) The pharmaceutical according to any one of (1) to (9), wherein the antibody is a monoclonal antibody or a polyclonal antibody.

[0023] (11) The pharmaceutical product according to any one of (1) to (10), wherein the antibody or fragment thereof is any one of the following (A) to (M): (A) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 36, 37, and 38, respectively, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 40, 41, and 42, respectively, and having immunological reactivity with CAPRIN-1 protein. (B) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 44, 45, and 46, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 48, 49, and 50, and having immunological reactivity with CAPRIN-1 protein. (C) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 52, 53, and 54, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 56, 57, and 58, respectively, and having immunological reactivity with CAPRIN-1 protein. (D) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 60, 61, and 62, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 64, 65, and 66, respectively, and having immunological reactivity with CAPRIN-1 protein. (E) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 170, 171, and 172, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 173, 174, and 175, and having immunological reactivity with CAPRIN-1 protein. (F) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 176, 177, and 178, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 179, 180, and 181, and having immunological reactivity with CAPRIN-1 protein. (G) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 182, 183, and 184, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 185, 186, and 187, and having immunological reactivity with CAPRIN-1 protein. (H) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 188, 189, and 190, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 191, 192, and 193, respectively, and having immunological reactivity with CAPRIN-1 protein. (I) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 146, 147, and 148, respectively, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 149, 150, and 151, respectively, and having immunological reactivity with CAPRIN-1 protein. (J) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 272, 273, and 274, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 275, 276, and 277, and having immunological reactivity with CAPRIN-1 protein. (K) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 290, 291, and 292, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 293, 294, and 295, and having immunological reactivity with a CAPRIN-1 protein. (L) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 301, 302, and 303, respectively, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 305, 306, and 307, respectively, and having immunological reactivity with CAPRIN-1 protein. (M) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 134, 135, and 136, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 137, 138, and 139, respectively, and having immunological reactivity with CAPRIN-1 protein.

[0024] (12) The pharmaceutical product according to any one of (1) to (11), wherein the antibody or the fragment thereof is any one of the following (a) to (a1): (a) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 39 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 43; (b) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 47 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 51; (c) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 55 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 59 (d) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 63 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 67 (e) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 68 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 69 (f) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 70 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 71; (g) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 72 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 73 (h) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 74 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 75 (i) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 76 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 77; (j) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 78 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 79 (k) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 80 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 81 (l) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 82 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 83 (m) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 84 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 85 (n) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 86 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 87 (o) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 88 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 89 (p) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 90 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 91 (q) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 92 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 93 (r) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 94 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 95 (s) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 96 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97 (t) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 98 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 99 (u) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 100 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 101 (v) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 102 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 103 (w) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 104 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 105 (x) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 106 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 107 (y) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 108 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 109 (z) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 110 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 111 (aa) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 112 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 113 (ab) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 114 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 115 (ac) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 116 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 117 (ad) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 118 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 119 (ae) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 120 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 121 (af) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 122 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 123 (ag) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 124 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 125 (ah) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 126 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 127 (ai) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 128 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129 (aj) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 130 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 131. (ak) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 132 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 133 (a1) An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 300 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 304.

[0025] (13) The pharmaceutical according to any one of (1) to (12), wherein the antibody is a human antibody, a humanized antibody, a chimeric antibody, or a single-chain antibody.

[0026] (14) The pharmaceutical agent according to any one of (1) to (13), wherein the cancer expresses CAPRIN-1 protein on the cell membrane surface.

[0027] (15) The pharmaceutical product according to any one of (1) to (14), wherein the cancer is melanoma, breast cancer, kidney cancer, colon cancer, pancreatic cancer, lung cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancer, gastric cancer, mesothelial cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, hepatocellular carcinoma, glioblastoma, urothelial carcinoma, ovarian cancer, bladder cancer, uterine cancer, primary central nervous system lymphoma, primary testicular lymphoma, biliary tract cancer, bile duct cancer, brain tumor, prostate cancer, leukemia, lymphoma, liver cancer, sarcoma, fibrosarcoma, mast cell tumor, adrenocortical carcinoma, Ewing's tumor, multiple myeloma, testicular cancer, thyroid cancer, basal cell carcinoma, Paget's disease, or skin cancer.

[0028] (16) A drug efficacy enhancer for a pharmaceutical composition for treating and / or preventing cancer, which comprises an immune checkpoint inhibitor as an active ingredient and an antibody or a fragment thereof that is immunologically reactive with CAPRIN-1 protein as an active ingredient.

[0029] (17) A pharmaceutical efficacy enhancer for a pharmaceutical composition for treating and / or preventing cancer, which comprises an immune checkpoint inhibitor as an active ingredient, and which comprises an antibody or a fragment thereof having immunological reactivity with CAPRIN-1 protein as an active ingredient.

[0030] (18) A method for treating and / or preventing cancer, comprising administering to a subject an antibody or a fragment thereof immunologically reactive with CAPRIN-1 protein and an immune checkpoint inhibitor, together or separately.

[0031] This specification includes the disclosure of Japanese Patent Application No. 2020-043022, from which this application claims priority. [Effects of the Invention]

[0032] The combined use of an antibody against the CAPRIN-1 protein or a fragment thereof according to the present invention with an immune checkpoint inhibitor exhibits a stronger antitumor effect than the use of an antibody against the CAPRIN-1 protein alone or an existing chemotherapeutic agent. Furthermore, the combined use of an antibody against the CAPRIN-1 protein or a fragment thereof according to the present invention with a drug containing an immune checkpoint inhibitor exhibits a stronger antitumor effect than the use of an existing anticancer drug therapy and an antibody against the CAPRIN-1 protein alone. Therefore, the combined use of an antibody against the CAPRIN-1 protein or a fragment thereof with an immune checkpoint inhibitor is effective in treating or preventing cancer. DETAILED DESCRIPTION OF THE INVENTION

[0033] The antitumor activity of the antibody against the CAPRIN-1 protein or its fragment (hereinafter referred to as "anti-CAPRIN-1 antibody") used in the present invention in combination with an immune checkpoint inhibitor can be evaluated by examining the inhibition of tumor growth in tumor-bearing animals in vivo, as described below.

[0034] As used herein, the terms "concomitant use" and "combination" refer to the administration of an anti-CAPRIN-1 antibody and an immune checkpoint inhibitor as independent active ingredients to the same living body simultaneously or at a predetermined interval. The intervals may be simultaneous administration, or may be 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 1 day, 3 days, 5 days, 7 days, 2 weeks, 3 weeks, or 4 weeks apart. Either the anti-CAPRIN-1 antibody or the combination of drugs including the immune checkpoint inhibitor may be administered when they exhibit their activity in vivo. Alternatively, the anti-CAPRIN-1 antibody or the drug including the immune checkpoint inhibitor may be administered first.

[0035] The term "combined together or separately" as used herein means that multiple drugs are contained in a form that can be administered to a patient simultaneously or separately, and this form may be, for example, a so-called mixed preparation in which multiple drugs are mixed, or a so-called kit preparation in which multiple drugs are contained as individual preparations. This form also includes kit preparations in which multiple drugs are contained in any combination in two or more preparations.

[0036] Such a kit preparation according to the present invention may be, for example, a kit preparation comprising a preparation (or pharmaceutical composition) containing an anti-CAPRIN-1 antibody and a preparation (or pharmaceutical composition) containing an immune checkpoint inhibitor. Furthermore, the kit preparation according to the present invention may also comprise, in addition to the anti-CAPRIN-1 antibody and the immune checkpoint inhibitor, other agents described below (other known antitumor agents or other immune checkpoint inhibitors).

[0037] The anti-CAPRIN-1 antibody of the present invention may be a monoclonal antibody or a polyclonal antibody, preferably a monoclonal antibody. The antibody of the present invention may be any type of antibody as long as it can exhibit anti-tumor activity, and the antibody may be a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, or a non-human animal antibody.

[0038] Furthermore, subjects to be treated and / or prevented for cancer in the present invention include mammals such as humans, pet animals, livestock, and sport animals, with humans being the preferred subject.

[0039] The following describes the present invention, including an anti-CAPRIN-1 antibody, a pharmaceutical containing an immune checkpoint inhibitor as an active ingredient, and a method for treating and / or preventing cancer.

[0040] <Anti-CAPRIN-1 antibody> Among CAPRIN-1 proteins having amino acid sequences represented by any of the even-numbered SEQ ID NOS: 2 to 30, which are specific examples of antigens immunologically reactive with the anti-CAPRIN-1 antibodies used in the present invention, the amino acid sequences represented by SEQ ID NOS: 6, 8, 10, 12, and 14 are those of canine CAPRIN-1 protein, the amino acid sequences represented by SEQ ID NOS: 2 and 4 are those of human CAPRIN-1 protein, the amino acid sequence represented by SEQ ID NOS: 16 is that of bovine CAPRIN-1 protein, the amino acid sequence represented by SEQ ID NOS: 18 is that of equine CAPRIN-1 protein, the amino acid sequences represented by SEQ ID NOS: 20, 22, 24, and 28 are those of mouse CAPRIN-1 protein, and the amino acid sequence represented by SEQ ID NOS: 30 is that of chicken CAPRIN-1 protein.

[0041] Furthermore, the anti-CAPRIN-1 antibody used in the present invention may be immunologically reactive with a variant of the CAPRIN-1 protein that has 80% or more, preferably 90% or more, more preferably 95% or more, and even more preferably 99% or more sequence identity with any of the amino acid sequences represented by any of the even-numbered SEQ ID NOs: 2 to 30. As used herein, "% sequence identity" refers to the percentage (%) of identical amino acids (or bases) relative to the total number of amino acids (or bases) when the two sequences are aligned to maximize similarity, with or without introducing gaps.

[0042] In the present invention, an anti-CAPRIN-1 antibody refers to an antibody or a fragment thereof (antigen-binding fragment) that is immunologically reactive with the full-length CAPRIN-1 protein or a fragment thereof. Here, "immunological reactivity" refers to the property of an antibody specifically binding to the CAPRIN-1 protein or a partial polypeptide thereof in vivo.

[0043] The anti-CAPRIN-1 antibody used in the present invention may be a monoclonal antibody or a polyclonal antibody.

[0044] Polyclonal antibodies (anti-CAPRIN-1 polyclonal antibodies) immunologically reactive with the full-length CAPRIN-1 protein or a fragment thereof can be obtained, for example, by immunizing mice, human antibody-producing mice, rats, rabbits, chickens, etc. with natural CAPRIN-1 protein, or a fusion protein with GST, or a partial peptide thereof, followed by collecting serum and purifying the serum using ammonium sulfate precipitation, protein A, protein G, a DEAE ion exchange column, or an affinity column bound to CAPRIN-1 protein or a partial peptide.

[0045] The nucleotide and amino acid sequences of CAPRIN-1 and its homologs can be obtained, for example, by accessing GenBank (NCBI, USA) and using algorithms such as BLAST and FASTA (Karlin and Altschul, Proc. Natl. Acad. Sci. USA, 90:5873-5877, 1993; Altschul et al., Nucleic Acids Res. 25:3389-3402, 1997). Methods for producing the CAPRIN-1 protein can be obtained by referring to WO2014 / 012479, and cells expressing the CAPRIN-1 protein can also be used.

[0046] Monoclonal antibodies immunologically reactive with the full-length CAPRIN-1 protein or a fragment thereof (anti-CAPRIN-1 monoclonal antibodies) can be obtained, for example, by immunizing mice with SK-BR-3 breast cancer cells expressing CAPRIN-1 or the full-length CAPRIN-1 protein or a fragment thereof, fusing spleen cells isolated from the mice with myeloma cells, and selecting clones producing anti-CAPRIN-1 monoclonal antibodies from the resulting fused cells (hybridomas). Antibodies produced by the selected hybridomas can be obtained by methods similar to those used for purifying polyclonal antibodies, as described above.

[0047] The antibodies used in the present invention include human antibodies, humanized antibodies, chimeric antibodies, and non-human animal antibodies.

[0048] Human antibodies can be obtained by sensitizing human lymphocytes infected with EB virus with the protein, protein-expressing cells, or their lysates, fusing the sensitized lymphocytes with myeloma cells such as human U266 cells, and obtaining antibodies immunologically reactive with the full-length CAPRIN-1 protein or fragments thereof from the resulting fused cells.

[0049] Humanized antibodies are modified antibodies, also known as reshaped human antibodies. Humanized antibodies are constructed by grafting the complementarity-determining regions (CDRs) of an antibody derived from an immunized animal onto the CDRs of a human antibody. Genetic recombination, a common technique for this purpose, is also well known. Specifically, for example, a DNA sequence designed to link the CDRs of a mouse or rabbit antibody with the framework regions of a human antibody is synthesized by PCR from several oligonucleotides engineered to have overlapping ends. The resulting DNA is ligated to DNA encoding the constant regions of a human antibody, incorporated into an expression vector, and then introduced into a host for production (see European Patent Application Publication No. EP239400 and International Publication No. WO96 / 02576). The framework regions of the human antibody linked via the CDRs are selected so that the CDRs form a good antigen-binding site. If necessary, amino acids in the framework regions of the variable regions of the antibody may be substituted so that the complementarity-determining regions of the reshaped human antibody form an appropriate antigen-binding site (Sato K. et al., Cancer Research 1993, 53: 851-856). Alternatively, the framework regions may be substituted with those from various human antibodies (see WO99 / 51743).

[0050] Antibodies are typically heteromeric glycoproteins containing at least two heavy chains and two light chains. Antibodies consist of two identical light chains and two identical heavy chains. A heavy chain has a heavy chain variable region at one end, followed by several constant regions. A light chain has a light chain variable region at one end, followed by several constant regions. The variable regions contain specific variable regions called complementarity-determining regions (CDRs), which confer binding specificity to the antibody. Relatively conserved portions of the variable regions are called framework regions (FRs). Each complete heavy and light chain variable region contains four FRs linked by three CDRs (CDR1 to CDR3).

[0051] The sequences of the constant and variable regions of human-derived heavy and light chains are available from, for example, NCBI (GenBank, UniGene, etc., in the United States). For example, reference can be made to the sequences of the human IgG1 heavy chain constant region under accession number J00228, the human IgG2 heavy chain constant region under accession number J00230, the human light chain κ constant region under accession numbers V00557, X64135, X64133, etc., and the human light chain λ constant region under accession numbers X64132 and X64134, etc.

[0052] Chimeric antibodies are antibodies produced by combining sequences derived from different animals, such as antibodies consisting of the heavy and light chain variable regions of a mouse antibody and the heavy and light chain variable region constant regions of a human antibody. Chimeric antibodies can be produced using known methods, for example, by linking DNA encoding an antibody V region with DNA encoding a human antibody C region, incorporating this into an expression vector, and introducing it into a host for production.

[0053] Non-human animal antibodies can be obtained by immunizing animals with a sensitizing antigen according to known methods. A typical method is to inject the sensitizing antigen intraperitoneally, intradermally, or subcutaneously into animals such as mice. When injecting the sensitizing antigen, the antigen is mixed with an appropriate amount of various adjuvants, such as Freund's complete adjuvant (CFA), and then administered to the animal multiple times. After immunizing an animal and confirming that the serum contains anti-CAPRIN-1 antibodies, the serum is obtained and purified using ammonium sulfate precipitation, protein A, protein G, a DEAE ion exchange column, or an affinity column coupled with CAPRIN-1 protein or a partial peptide, as described above, to obtain non-human animal antibodies. Furthermore, monoclonal antibodies can be obtained from non-human animals by collecting immune cells from the immunized animal and subjecting them to cell fusion with myeloma cells. Cell fusion between the immune cells and myeloma cells can be performed according to known methods (see Kohler, G. and Milstein, C. Methods Enzymol. (1981) 73, 3-46).

[0054] The antibodies used in the present invention can also be obtained as recombinant antibodies produced by cloning antibody genes from hybridomas, incorporating them into appropriate vectors, and introducing them into a host using genetic engineering techniques (see Carl, A.K. Borrebaeck, James, W. Larrick, THERAPEUTIC MONOCLONAL ANTIBODIES, Published in the United Kingdom by MACMILLAN PUBLISHERS LTD, 1990).

[0055] The anti-CAPRIN-1 antibody used in the present invention may have amino acids in the variable region (e.g., FR) or constant region substituted with other amino acids. The amino acid substitutions are single or multiple, for example, fewer than 15, fewer than 10, 8 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, or 2 or fewer amino acids, preferably 1 to 9 amino acids. The substituted antibody should have the same or higher antigen-specific binding properties and antigen-binding affinity as the unsubstituted antibody, and should not induce rejection in humans. Conservative amino acid substitutions are preferred, which are substitutions between amino acids with similar properties, such as charge, side chain, polarity, and aromaticity. Amino acids with similar properties can be classified into, for example, basic amino acids (arginine, lysine, histidine), acidic amino acids (aspartic acid, glutamic acid), uncharged polar amino acids (glycine, asparagine, glutamine, serine, threonine, cysteine, tyrosine), nonpolar amino acids (leucine, isoleucine, alanine, valine, proline, phenylalanine, tryptophan, methionine), branched-chain amino acids (threonine, valine, isoleucine), and aromatic amino acids (phenylalanine, tyrosine, tryptophan, histidine).

[0056] The anti-CAPRIN-1 antibody used in the present invention is expected to have a stronger antitumor effect if it has a higher binding affinity with the CAPRIN-1 protein on the surface of cancer cells. The binding constant (affinity constant) Ka (k / k) is preferably at least 10 7 M -1 , at least 10 8 M -1 , at least 5 × 10 8 M -1 , at least 10 9 M -1 , at least 5 × 10 9 M -1 , at least 10 10 M -1 , at least 5 × 10 10 M -1 , at least 10 11 M -1 , at least 5 × 10 11 M -1, at least 10 12 M -1 , or at least 10 13 M -1 It is desirable that:

[0057] The anti-CAPRIN-1 antibody used in the present invention may be chemically modified. Examples of such modified antibodies include antibodies conjugated to various molecules, such as polyethylene glycol (PEG) and antitumor compounds (e.g., the antitumor agents exemplified below). The conjugated substance in the modified antibody of the present invention is not limited. Such modified antibodies can be obtained by chemically modifying the antibody. These methods have already been established in the field.

[0058] The binding ability of the anti-CAPRIN-1 antibody used in the present invention to effector cells can be improved by substituting one, two, or several amino acids in the heavy chain constant region of the antibody, or by removing fucose bound to N-acetylglucosamine in the N-glycoside-linked sugar chain bound to the heavy chain constant region. The above may be achieved by amino acid substitution alone, or may be a composition with an antibody bound to fucose.

[0059] Antibodies in which one, two, or several amino acids in the heavy chain constant region have been substituted can be produced by referring to, for example, WO2004 / 063351, WO2011 / 120135, U.S. Patent No. 8,388,955, WO2011 / 005481, U.S. Patent No. 6,737,056, and WO2005 / 063351.

[0060] Antibodies from which fucose attached to N-acetylglucosamine in N-glycoside-linked sugar chains in the heavy chain constant region has been removed, or cells producing such antibodies, can be prepared with reference to U.S. Patent No. 6,602,684, European Patent No. 1,914,244, and U.S. Patent No. 7,579,170. Antibodies from which fucose attached to N-acetylglucosamine in N-glycoside-linked sugar chains attached to the heavy chain constant region has been removed, and compositions of antibodies to which fucose has been bound, or cells producing such antibodies, can be prepared with reference to, for example, U.S. Patent No. 8,642,292.

[0061] The anti-CAPRIN-1 polyclonal antibody, anti-CAPRIN-1 monoclonal antibody, antibody production method, purification method, and method for producing the CAPRIN-1 protein or its partial polypeptide used in immunization used in the present invention are disclosed in WO2010 / 016526, WO2011 / 096517, WO2011 / 096528, WO2011 / 096519, WO2011 / 096533, WO2011 / 096534, and WO2011 / 09653 5, WO2013 / 018886, WO2013 / 018894, WO2013 / 018892, WO2013 / 018891, WO2013 / 018889, WO2013 / 018883, WO2013 / 125636, WO2013 / 125654, WO2013 / 125630, WO2013 / 125640, WO2013 / 147169, WO2013 / 147176 and WO2015 / 020212.

[0062] Specific examples of anti-CAPRIN-1 antibodies of the present invention include those described in WO2010 / 016526, WO2011 / 096517, WO2011 / 096528, WO2011 / 096519, WO2011 / 096533, WO2011 / 096534, WO2011 / 096535, WO2013 / 018886, WO2013 / 018894, WO2013 / 018892, and WO2013 / 018891. , WO2013 / 018889, WO2013 / 018883, WO2013 / 125636, WO2013 / 125654, WO2013 / 125630, WO2013 / 125640, WO2013 / 147169, WO2013 / 147176, and WO2015 / 020212, but preferred anti-CAPRIN-1 antibodies include the following:

[0063] An antibody or fragment thereof that is immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having an amino acid sequence represented by SEQ ID NO: 2 or SEQ ID NO: 4, or an amino acid sequence that has 80% or more (preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, and even more preferably 99% or more) sequence identity with said amino acid sequence.

[0064] An antibody or fragment thereof immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 31 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity with said amino acid sequence. An antibody or fragment thereof immunologically reactive with a CAPRIN-1 protein, preferably comprising a heavy chain variable region containing the complementarity determining regions of SEQ ID NOs: 36, 37, and 38 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region containing the complementarity determining regions of SEQ ID NOs: 40, 41, and 42 (CDR1, CDR2, and CDR3, respectively), or an antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions of SEQ ID NOs: 140, 141, and 142 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region containing the complementarity determining regions of SEQ ID NOs: 143, 144, and 145. an antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 164, 165, and 166 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 167, 168, and 169 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with CAPRIN-1 protein; or an antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 164, 165, and 166 (CDR1, CDR2, and CDR3, respectively), and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 167, 168, and 169 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with CAPRIN-1 protein. More preferably, the antibody or fragment thereof has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 39 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 43, or a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 70 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 71, or a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 78 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 79.

[0065] An antibody or fragment thereof immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 33 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity to said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 60, 61, and 62 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 64, 65, and 66 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 63 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 67.

[0066] An antibody or fragment thereof immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 32 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity to said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 52, 53, and 54 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 56, 57, and 58 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 59.

[0067] An antibody or fragment thereof that is immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence represented by SEQ ID NO: 34 or an amino acid sequence that has 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity with said amino acid sequence. Preferably, an antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 170, 171, and 172 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 173, 174, and 175 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with the CAPRIN-1 protein; or an antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 176, 177, and 178 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 179, 180, and 181 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with the CAPRIN-1 protein. More preferably, the antibody or fragment thereof has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 80 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 81, or an antibody or fragment thereof has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 82 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 83.

[0068] An antibody or fragment thereof that is immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence represented by SEQ ID NO: 35 or an amino acid sequence that has 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity with said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 182, 183, and 184 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 185, 186, and 187 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with the CAPRIN-1 protein; or an antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 188, 189, and 190 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 191, 192, and 193 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with the CAPRIN-1 protein. More preferably, the antibody or fragment thereof has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 84 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 85, or an antibody or fragment thereof has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 86 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 87.

[0069] An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 44, 45, and 46, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 48, 49, and 50, and having immunological reactivity with CAPRIN-1 protein. Preferably, the antibody or fragment thereof comprises the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 47, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 51.

[0070] An antibody or fragment thereof immunologically reactive with a partial polypeptide of the CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 296 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity to said amino acid sequence. An antibody or fragment thereof preferably comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 146, 147, and 148 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 149, 150, and 151 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with the CAPRIN-1 protein. More preferably, an antibody or fragment thereof whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 72 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 73.

[0071] An antibody or fragment thereof immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 297 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity to said amino acid sequence. An antibody or fragment thereof preferably comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 272, 273, and 274 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 275, 276, and 277 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with a CAPRIN-1 protein. More preferably, an antibody or fragment thereof whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 114 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 115.

[0072] An antibody or fragment thereof immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 298 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity to said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 290, 291, and 292 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 293, 294, and 295 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 120 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 121.

[0073] An antibody or fragment thereof immunologically reactive with a partial polypeptide of the CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 299 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity to said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 301, 302, and 303 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 305, 306, and 307 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with the CAPRIN-1 protein. More preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 300 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 304.

[0074] An antibody or fragment thereof immunologically reactive with a partial polypeptide of the CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 308 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity to said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 134, 135, and 136 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 137, 138, and 139 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with the CAPRIN-1 protein. More preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 68 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 69.

[0075] An antibody or fragment thereof immunologically reactive with a partial polypeptide of the CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 309 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity to said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 134, 135, and 136 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 137, 138, and 139 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with the CAPRIN-1 protein. More preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 68 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 69.

[0076] In addition, the following anti-CAPRIN-1 antibodies are also preferably used.

[0077] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 68 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 69.

[0078] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 70 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 71.

[0079] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 72 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 73.

[0080] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 74 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 75.

[0081] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 76 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 77.

[0082] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 78 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 79.

[0083] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 80 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 81.

[0084] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 82 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 83.

[0085] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 84 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 85.

[0086] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 86 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 87.

[0087] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 88 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 89.

[0088] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 90 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 91.

[0089] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 92 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 93.

[0090] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 94 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 95.

[0091] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 96 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97.

[0092] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 98 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 99.

[0093] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 100 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 101.

[0094] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 102 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 103.

[0095] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 104 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 105.

[0096] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 106 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 107.

[0097] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 108 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 109.

[0098] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 110 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 111.

[0099] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 112 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 113.

[0100] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 114 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 115.

[0101] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 116 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 117.

[0102] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 118 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 119.

[0103] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 120 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 121.

[0104] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 122 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 123.

[0105] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 124 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 125.

[0106] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 126 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 127.

[0107] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 128 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129.

[0108] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 130 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 131.

[0109] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 132 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 133.

[0110] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 300 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 304.

[0111] In the Examples described below, it was confirmed that the above-mentioned polyclonal or monoclonal antibodies against the full-length CAPRIN-1 protein or a portion of the polypeptide region expressed on the cell membrane surface of cancer cells exhibit reactivity with the cell membrane surface of multiple human cancer cells, and effective results were obtained in human cancer patients, with a remarkable antitumor effect resulting in the complete disappearance of tumors in some cancer sites.

[0112] <Immune checkpoint> The term "immune checkpoint" refers to a function expressed by immune cells and cancer cells in the body that distinguishes between antigens and stimulates or inhibits stimulation. Specifically, "PD-L1," "PD-L2," "CD80," or "CD86" are expressed on the cell membrane surface of antigen-presenting cells such as dendritic cells, macrophages, or cancer cells as molecules that activate immune checkpoints. Meanwhile, immune cells such as T lymphocytes express molecules that interact with "PD-L1," "PD-L2," "CD80," or "CD86," namely, "PD-1 (Programmed Death-1)," "CD28," and "CTLA-4 (Cytotoxic T-lymphocyte-associated antigen-4)." These molecules are known as immune checkpoint molecules.

[0113] Here, interaction refers to the action of paired molecules binding or dissociating to stimulate or inhibit the function of each other's cells. For example, in vivo, cancer cells often express "PD-L1" or "PD-L2." When "PD-1" expressed on T cells binds to these molecules, the T cells' cytokine production ability is reduced, and a signal that suppresses T cell activity is transmitted intracellularly. Cancer cells often express PD-L1 molecules and, through the above-mentioned interaction, escape the surveillance and attack functions of T cells in vivo.

[0114] In addition, CTLA-4, one of the immune checkpoint molecules, is expressed on activated T cells or immunosuppressive T cells (regulatory T cells). The molecules that CTLA-4 interacts with, CD80 or CD86, are expressed on antigen-presenting cells, and CTLA-4 binds to CD80 or CD86. CTLA-4 often binds more strongly than CD28, a molecule that also interacts with CD80 and CD86, suppressing the maturation of antigen-presenting cells and, as a result, suppressing T cell activation.

[0115] PD-L1 is expressed on antigen-presenting cells and various cancer cells, including those in lung cancer, colon cancer, and malignant melanoma, while PD-L2 is expressed on activated antigen-presenting cells, macrophages, and cancer cells.

[0116] <Immune checkpoint inhibitors> Drugs that inhibit the function of immune checkpoints to release the suppressed state in vivo are called "immune checkpoint inhibitors." Examples of immune checkpoint inhibitors include inhibitors of PD-L1, preferably anti-PD-L1 antibodies; inhibitors of PD-1, preferably anti-PD-1 antibodies; and inhibitors of CTLA-4, preferably anti-CTLA-4 antibodies.

[0117] The anti-PD-1 antibody is preferably nivolumab, pembrolizumab, spitalizumab, or cemiplimab.

[0118] The anti-PD-L1 antibody is preferably avelumab, atezolizumab, or durvalumab.

[0119] The anti-CTLA-4 antibody is preferably ipilimumab or tremelimumab.

[0120] Other antibodies that act as immune checkpoint inhibitors include anti-PD-1 / CTLA-4 bispecific antibodies (e.g., MEDI5752).

[0121] <Other drugs> The pharmaceutical agent of the present invention, which contains the anti-CAPRIN-1 antibody and the immune checkpoint inhibitor as active ingredients, may be used in combination with one or more other immune checkpoint inhibitors, or may be used in combination with an antitumor agent known in the literature, etc. The known antitumor agents are not particularly limited, and specific examples include padoxorubicin, daunorubicin, cyclophosphamide, methotrexate, thiotepa, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, bullatacin, bullatasinone, camptothecin, bryostatin, callystatin, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, and chlornaphazine. ), colofsphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine mustine, lomustine, nimustine, ranimustine, calicheamicin, dynemicin, clodronate, esperamicin, aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin,Detorbicin, 6-diazo-5-oxo-L-norleucine, adriamycin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, denopterin, pteropterin, trimetrexate, Fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, dideoxyuridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, florinic acid acid), aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elfornithine, elliptinium acetate, epothilone, etoglucid, lentinan, lonidamine, maytansine,Ansamitocin, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonic acid acid), triaziquone, roridine A, anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, doxetaxel, chlorambucil, 6-thioguanine, mercaptopurine, oxaliplatin, vinblastine, etoposide cycloheximide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, irinotecan, topoisomerase inhibitors, difluoromethylmethylnitine (DMFO), retinoic acid, and pharmaceutically acceptable (known) salts or (known) derivatives thereof.

[0122] <Anti-tumor effect of the present invention> The combination of the anti-CAPRIN-1 antibody of the present invention and an immune checkpoint inhibitor has cytotoxic activity in vivo. Therefore, the anti-tumor effect of the present invention can be determined by examining the cytotoxic activity against cancer. Cytotoxic activity can be evaluated by administering a drug containing an anti-CAPRIN-1 antibody and an immune checkpoint inhibitor to a living body with cancer, measuring the tumor size after administration, and examining the cancer size over time. The anti-tumor effect of the present invention can also be evaluated by examining the survival rate. It can also be evaluated by examining the ability to produce cytokines or chemokines. The anti-tumor effect of the combination of the anti-CAPRIN-1 antibody of the present invention and an immune checkpoint inhibitor, or the anti-tumor effect of the combination of the anti-CAPRIN-1 antibody of the present invention and a drug containing an immune checkpoint inhibitor with one or more other drugs, can be further determined by examining the prevention of cancer, metastasis, or recurrence.

[0123] The anti-CAPRIN-1 antibody used in the present invention is expected to have a stronger antitumor effect if it has a higher binding affinity with the CAPRIN-1 protein on the surface of cancer cells. The binding constant (affinity constant) Ka (k / k) is preferably at least 10 7 M -1 , at least 10 8 M -1 , at least 5 × 10 8 M -1 , at least 10 9 M -1 , at least 5 × 10 9 M -1 , at least 10 10 M -1 , at least 5 × 10 10 M -1 , at least 10 11 M -1 , at least 5 × 10 11 M -1 , at least 10 12 M -1 , or at least 10 13 M -1 It is desirable that:

[0124] The ability of the anti-CAPRIN-1 antibody used in the present invention to bind to CAPRIN-1 can be determined using binding assays such as ELISA, Western blotting, immunofluorescence, and flow cytometry.

[0125] As described above, administration of a combination of an anti-CAPRIN-1 antibody of the present invention, an angiogenesis inhibitor, and carboplatin to a living body with cancer enhances the anti-tumor effect compared to the anti-CAPRIN-1 antibody alone, with the enhancement rate being preferably 30% or more, more preferably 40% or more, even more preferably 50% or more, even more preferably 55% or more, even more preferably 60% or more, even more preferably 65% ​​or more, and most preferably 70% or more. The enhancement rate of the anti-tumor effect of the combination of an anti-CAPRIN-1 antibody of the present invention, an angiogenesis inhibitor, and carboplatin compared to the administration of the anti-CAPRIN-1 antibody alone can be calculated by administering effective amounts of each antibody to tumor-bearing mice under the same conditions and comparing the tumor volumes 7 days or later after the start of administration.

[0126] <Medicines for the treatment and / or prevention of cancer> The pharmaceutical product of the present invention is intended to treat and / or prevent cancer. The cancer targeted by the pharmaceutical product of the present invention is not particularly limited as long as it is a cancer (cell) that expresses CAPRIN-1 protein or a cancer that expresses immune checkpoint molecules (e.g., PD-L1, PD-L2).

[0127] As used herein, "treatment" refers to the treatment of cancer based on the antitumor effect described above. Furthermore, as used herein, "prevention" refers not only to the prevention of cancer onset, but also to the prevention of cancer metastasis or recurrence.

[0128] As used herein, the terms "tumor" and "cancer" refer to malignant neoplasms and are used interchangeably.

[0129] The cancer patients targeted by the present invention are not particularly limited, but are preferably cancer patients with a history of cancer treatment with pharmaceuticals other than cancer treatment with pharmaceuticals containing an antibody or fragment thereof immunologically reactive with CAPRIN-1 protein and an immune checkpoint inhibitor, and also include patients who have previously been treated with chemotherapy, molecular targeted drugs, or hormone therapy. Examples include cancer patients who have received cancer treatment in accordance with the "NCCN Clinical Practice Guidelines in Oncology," "ESMO Clinical Practice Guidelines," or "Cancer Treatment Guidelines." Preferably, the cancer patients have a history of cancer treatment with an immune checkpoint inhibitor.

[0130] Furthermore, the patient is preferably a cancer patient who has not responded to cancer treatment with a pharmaceutical other than cancer treatment with a pharmaceutical containing an anti-CAPRIN-1 antibody and an immune checkpoint inhibitor, either together or separately, and more preferably a cancer patient who has not responded to cancer treatment with an immune checkpoint inhibitor.

[0131] Furthermore, the patient is preferably a cancer patient having cancer that is resistant to cancer treatment with a pharmaceutical agent other than cancer treatment with a pharmaceutical agent containing an anti-CAPRIN-1 antibody and an immune checkpoint inhibitor, either together or separately, and more preferably a cancer patient having cancer that is resistant to cancer treatment with an immune checkpoint inhibitor. Here, the terms "cancer treatment was ineffective" and "resistant to cancer treatment" are used interchangeably.

[0132] The cancer that is the subject of the present invention may be any cancer in which the CAPRIN-1 protein is expressed on the cell membrane surface. Preferred cancers are melanoma (including postoperative melanoma), lung cancer (including non-small cell lung cancer and small cell lung cancer), renal cell carcinoma, Hodgkin's lymphoma, head and neck cancer, gastric cancer, mesothelial carcinoma (including malignant pleural mesothelioma), colorectal cancer (e.g., MSI-high colorectal cancer), esophageal cancer, gastroesophageal junction cancer, hepatocellular carcinoma, glioblastoma, urothelial carcinoma, ovarian cancer, bladder cancer, uterine cancer (including cervical cancer and endometrial cancer), primary central nervous system lymphoma, primary testicular lymphoma, pancreatic cancer, biliary tract cancer, bile duct cancer, breast cancer, kidney cancer, colorectal cancer, brain tumor, prostate cancer, leukemia, lymphoma, liver cancer, sarcoma, fibrosarcoma, mast cell tumor, adrenocortical carcinoma, Ewing's tumor, multiple myeloma, testicular cancer, thyroid cancer, basal cell carcinoma, Paget's disease, and skin cancer. These cancers may be primary cancers, metastatic cancers, metastatic or recurrent cancers, postoperative cancers, or unresectable cancers. Note that melanoma is often used synonymously with malignant melanoma or malignant melanoma.

[0133] Other cancers that are the subject of the present invention include cancers that are resistant to known treatments. Resistant cancers may be derived from patients with any treatment history, and are not particularly limited to these, but include, for example, cancers derived from patients with a history of treatment with an immune checkpoint inhibitor that did not respond to the treatment, have become resistant to the treatment, have metastasized, or have recurred.

[0134] More specifically, the cancers include, for example, Bowen's disease, squamous cell carcinoma, extramammary Paget's disease, mycosis fungoides, Sezary syndrome, cutaneous T / NK cell lymphoma, T-cell leukemia / lymphoma with lesions only in the skin, cutaneous B-cell lymphoma (indolent group), cutaneous T-cell lymphoma of the breast, combined breast adenocarcinoma, malignant mixed breast tumor, intraductal papillary adenocarcinoma, lung adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell carcinoma, and neuroepithelial tissue tumors such as glioma and glioblastoma. , neuroblastoma, ependymoma, neuronal cell tumor, embryonal neuroectodermal tumor, schwannoma, neurofibroma, meningioma, chronic lymphocytic leukemia, lymphoma, gastrointestinal lymphoma, gastrointestinal lymphoma, small to medium cell lymphoma, cecal cancer, ascending colon cancer, descending colon cancer, transverse colon cancer, sigmoid colon cancer, rectal cancer, ovarian epithelial cancer, germ cell tumor, stromal cell tumor, pancreatic ductal carcinoma, invasive pancreatic ductal carcinoma, adenocarcinoma of the pancreas, acinar cell carcinoma, adenosquamous carcinoma, giant cell tumor, intraductal papillary mucinous tumor Tumor, mucinous cystadenocarcinoma, pancreatoblastoma, pancreatic head cell tumor, Frants tumor, serous cystadenocarcinoma, solid papillary carcinoma, gastrinoma, glucagonoma, insulinoma, multiple endocrine neoplasia 1 (Wermer syndrome), non-functioning islet cell tumor, somatostatinoma, VIP-producing tumor, cervical cancer, endometrial cancer, fibrosarcoma, bone and joint sarcoma, Ewing's sarcoma, Wilms' tumor, hepatoblastoma, soft tissue sarcoma, acute leukemia, chronic leukemia, spinal cord tumor, soft tissue malignant tumor, Teratomas and head and neck cancers include, but are not limited to, hypopharyngeal cancer, oropharyngeal cancer, tongue cancer, nasopharyngeal cancer, oral cancer, lip cancer, paranasal sinus cancer, laryngeal cancer, renal pelvis and urinary tract cancer, bladder cancer, urethral cancer, testicular tumor, malignant pleural mesothelioma, malignant bone tumor, uterine cancer (postoperative chemotherapy, chemotherapy for metastasis or recurrence), pediatric malignant solid tumors (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, medulloblastoma, nephroblastoma, retinoblastoma, central nervous system germ cell tumor, Ewing's sarcoma family tumors), etc. Also included are palpable cancers, subcutaneous cancers, intracutaneous cancers, superficial cancers, dermal cancers, non-parenchymal cancers, and progressive cancers that originate from the above cancers. Furthermore, palpable cancers, subcutaneous cancers, intracutaneous cancers, superficial cancers, dermal cancers, and non-parenchymal cancers that have metastasized or recurred from the above cancers are also included.

[0135] Furthermore, preferred subjects (patients) are mammals, including, for example, primates, pet animals, livestock, sport animals, etc., with humans, dogs, and cats being particularly preferred.

[0136] The pharmaceuticals of the present invention can be formulated by methods known to those skilled in the art. The pharmaceuticals of the present invention can be used parenterally, for example, in the form of an injection of a sterile solution or suspension in water or other pharmaceutically acceptable liquid. For each formulation or pharmaceutical composition of the pharmaceuticals of the present invention, the active ingredient (at least one of the anti-CAPRIN-1 antibody and immune checkpoint inhibitor of the present invention) may be appropriately combined with, for example, a pharmacologically acceptable carrier, vehicle, or additive, specifically, sterile water, physiological saline, isotonic solution, buffer (buffer solution, etc.), vegetable oil, oily liquid, antioxidant, solubilizer, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, binder, etc., and preferably formulated by mixing with them in a unit dosage form required for generally accepted pharmaceutical practice. The amount of the active ingredient in these formulations is such that an appropriate dose within the indicated range can be obtained.

[0137] Sterile compositions for injection can be formulated according to standard pharmaceutical practice using a vehicle such as distilled water for injection. Aqueous solutions for injection include, for example, physiological saline, isotonic solutions containing glucose or other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride. These solutions may be used in combination with appropriate solubilizers, such as alcohols (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants (e.g., Polysorbate 80™ and HCO-60). Oily solutions include sesame oil and soybean oil, which may be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. Buffers such as phosphate buffer and sodium acetate buffer, soothing agents (e.g., procaine hydrochloride), stabilizers (e.g., benzyl alcohol, phenol), and antioxidants may also be added. The prepared injection solutions are usually filled into appropriate ampoules.

[0138] Administration may be oral or parenteral, preferably parenteral, and specific examples include injections, nasal administration, pulmonary administration, and transdermal administration. Examples of injections include intravenous, intramuscular, intraperitoneal, subcutaneous, and intratumoral injections, which can be administered systemically or locally. Examples of transdermal administrations include topical liniments and topical agents. Topical agents include solids, liquids, sprays, ointments, creams, and gels.

[0139] Furthermore, the administration method can be selected appropriately depending on the patient's age, body weight, sex, symptoms, etc. The dosage of a pharmaceutical composition containing at least one of an anti-CAPRIN-1 antibody and an immune checkpoint inhibitor can be selected, for example, from the range of 0.0001 mg to 1,000 mg per kg of body weight per administration, in terms of the amount of each active ingredient. Alternatively, the dosage of each active ingredient can be selected, for example, from the range of 0.001 to 100,000 mg / body weight per patient, or from 1 mg to 30 mg per kg of body weight, but is not necessarily limited to these values. The dosage and administration method vary depending on the patient's body weight, age, sex, symptoms, etc., but can be appropriately selected by those skilled in the art.

[0140] <Administration method> The treatment and / or prevention of cancer using the pharmaceutical compositions for cancer treatment and / or prevention of the present invention includes various forms in addition to the administration of the aforementioned pharmaceutical compositions. For example, the active ingredients of the pharmaceutical compositions of the present invention can be administered simultaneously, in parallel, or separately in a sequential order. Specifically, the second active ingredient can be administered within a time interval of up to about three weeks, i.e., immediately after the administration of the first active ingredient and up to about three weeks after. This administration may be performed following a surgical procedure, or a surgical procedure may be performed between the administration of the first and second agents. Furthermore, the pharmaceutical compositions for cancer treatment and / or prevention of the present invention may be administered in multiple administration cycles. For example, when the active ingredients of the pharmaceutical compositions for cancer treatment and / or prevention of the present invention are administered simultaneously, a pharmaceutical composition containing the active ingredients of the present invention (the anti-CAPRIN-1 antibody and immune checkpoint inhibitor of the present invention) is administered for about two days to about three weeks as one cycle. Thereafter, the treatment cycle can be repeated as necessary, according to the judgment of the physician in charge. Similarly, when a sequential regimen is planned, the administration period of each individual drug is adjusted so that it lasts for the same period. The interval between cycles can vary from 0 to 2 months. The dosage of each active ingredient of the pharmaceutical product for treating and / or preventing cancer of the present invention can be set in the same manner as the dosage of each active ingredient in the above-mentioned pharmaceutical composition.

[0141] <Pharmaceutical Kit> The pharmaceutical product for treating and / or preventing cancer of the present invention may be in the form of a pharmaceutical kit. A pharmaceutical kit is a package for using active ingredients in the form of separate pharmaceutical compositions (formulations) in a method for treating and / or preventing cancer, and the package may include instructions for administering each active ingredient. Each active ingredient of the pharmaceutical composition for treating and / or preventing cancer included in the pharmaceutical kit may be in the form of a pharmaceutical composition formulated as described above so that the active ingredients can be administered together or separately. The pharmaceutical kit also contains an amount of each active ingredient sufficient for one or more doses so that each active ingredient can be administered according to the administration method described above.

[0142] Based on the details specifically described above, the present invention provides a method for treating and / or preventing cancer, comprising administering the pharmaceutical composition of the present invention, or the anti-CAPRIN-1 antibody of the present invention and an immune checkpoint inhibitor to a subject (patient). For example, the present invention further provides a method for treating and / or preventing cancer, comprising administering the pharmaceutical composition of the present invention to a subject (patient) who has cancer or is suspected of having cancer. In the method of the present invention, in addition to the anti-CAPRIN-1 antibody of the present invention and the immune checkpoint inhibitor, another anti-tumor agent (such as a known anti-tumor agent) may also be administered to the subject (patient). In this embodiment, for example, the anti-CAPRIN-1 antibody of the present invention (antibody or fragment thereof), the immune checkpoint inhibitor, and optionally the other anti-tumor agent contained in the pharmaceutical composition may be administered to the subject (patient) simultaneously or separately. [Example]

[0143] The present invention will be specifically described below based on examples, but the scope of the present invention is not limited to these specific examples.

[0144] (Example 1) Preparation of anti-CAPRIN-1 antibody The anti-CAPRIN-1 antibody immunologically reactive with the CAPRIN-1 protein used in the present invention was prepared as follows.

[0145] (polyclonal antibody) One mg of human CAPRIN-1 recombinant protein (SEQ ID NO: 2) prepared according to Example 3 of WO2010 / 016526 was mixed with an equal volume of incomplete Freund's adjuvant (IFA) solution and administered subcutaneously to rabbits four times every two weeks. Blood was then collected to obtain antisera containing polyclonal antibodies. This antisera was further purified using Protein G carrier (GE Healthcare Biosciences) and substituted with PBS(-) to obtain a polyclonal antibody against CAPRIN-1 protein (anti-CAPRIN-1 polyclonal antibody #1).

[0146] (monoclonal antibody)100 μg of human CAPRIN-1 recombinant protein prepared according to Example 3 of WO2010 / 016526 was mixed with an equal amount of MPL+TDM adjuvant (Sigma), and this was used as the antigen solution per mouse. The antigen solution was administered intraperitoneally to 6-week-old Balb / c mice (Japan SLC), followed by three and 24 additional weekly administrations to complete the immunization. Three days after the final immunization, each spleen was removed and crushed between two sterilized glass slides. The spleen was washed with PBS(-) (Nissui), centrifuged at 1500 rpm for 10 minutes, and the supernatant was removed. This procedure was repeated three times to obtain spleen cells. The resulting spleen cells were mixed with mouse myeloma cells SP2 / 0 (purchased from ATCC) at a 10:1 ratio. A PEG solution (200 μl of RPMI 1640 medium containing 10% FBS and 800 μl of PEG 1500 (Boehringer) preheated to 37°C) was added and allowed to stand for 5 minutes to allow cell fusion. After centrifugation at 1700 rpm for 5 minutes and removal of the supernatant, the cells were suspended in 150 ml of RPMI 1640 medium containing 15% FBS and 2% equivalent of Gibco HAT solution (HAT selection medium). The cells were seeded onto 15 96-well plates (Nunc) at 100 μl per well. The mixture was cultured for 7 days at 37°C in 5% CO2 to obtain hybridomas representing fusion of spleen cells and myeloma cells. Hybridomas were selected based on the binding affinity of the antibodies produced by the hybridomas to the CAPRIN-1 protein. 100 μl of 1 μg / ml CAPRIN-1 protein solution was added per well of a 96-well plate and incubated at 4°C for 18 hours. After washing each well three times with PBS-T, 400 μl of 0.5% bovine serum albumin (BSA) solution (Sigma) was added per well and incubated at room temperature for 3 hours. After removing the solution and washing each well three times with 400 μl of PBS-T, 100 μl of each hybridoma culture supernatant was added per well and incubated at room temperature for 2 hours. After washing each well three times with PBS-T, 100 μl of HRP-labeled anti-mouse IgG (H+L) antibody (Invitrogen) diluted 5000-fold with PBS was added per well and incubated at room temperature for 1 hour.After washing the wells three times with PBS-T, 100 μl of TMB substrate solution (Thermo) was added per well and allowed to stand for 15–30 minutes for color development. After color development, 100 μl of 1 N sulfuric acid was added per well to stop the reaction, and the absorbance at 450 nm and 595 nm was measured using an absorption spectrometer. Several hybridomas producing antibodies with high absorbance values ​​were selected. The selected hybridomas were added to a 96-well plate at a density of 0.5 cells per well and cultured. After one week, hybridomas forming single colonies were observed in the wells. The cells in these wells were further cultured, and hybridomas were selected based on the binding affinity of the antibodies produced by the cloned hybridomas to the CAPRIN-1 protein. 100 μl of 1 μg / ml CAPRIN-1 protein solution was added per well of the 96-well plate and allowed to stand at 4°C for 18 hours. After washing each well three times with PBS-T, 400 μl of 0.5% BSA solution was added per well and incubated at room temperature for 3 hours. The solution was removed, and the wells were washed three times with 400 μl of PBS-T. 100 μl of each hybridoma culture supernatant obtained above was added per well and incubated at room temperature for 2 hours. After washing each well three times with PBS-T, 100 μl of HRP-labeled anti-mouse IgG (H+L) antibody (Invitrogen) diluted 5000-fold with PBS was added per well and incubated at room temperature for 1 hour. After washing each well three times with PBS-T, 100 μl of TMB substrate solution (Thermo) was added per well and incubated for 15–30 minutes to allow the color reaction to develop. After color development, 100 μl of 1 N sulfuric acid was added per well to stop the reaction, and the absorbance at 450 nm and 595 nm was measured using an absorbance meter. As a result, several mouse monoclonal antibodies reactive with the CAPRIN-1 protein were obtained.

[0147] Furthermore, flow cytometry was used to confirm the reactivity of these monoclonal antibodies with human cancer cells in which CAPRIN-1 protein has been confirmed to be expressed on the cell membrane surface. A mouse IgG control antibody that does not show reactivity with the cancer cells was used as a negative control. As a result of this confirmation, several monoclonal antibodies were obtained that showed stronger fluorescence intensity with the cancer cells than the mouse IgG control antibody and strongly reacted with the cell membrane surface of the cancer cells in which CAPRIN-1 is expressed on the cell membrane surface. From these, a monoclonal antibody reactive with CAPRIN-1 protein was selected: a monoclonal antibody against CAPRIN-1 described in WO2013 / 125630, which comprises the amino acid sequence of the heavy chain variable region represented by SEQ ID NO: 114 and the amino acid sequence of the light chain variable region represented by SEQ ID NO: 115.

[0148] CDRs 1 to 3 of the heavy chain variable region of the selected antibody were identified, and a nucleotide sequence was designed to enable expression of a heavy chain variable region whose framework region contained a human antibody sequence. This was then inserted into a mammalian expression vector containing the heavy chain constant region of human IgG1. Similarly, CDRs 1 to 3 of the light chain variable region were identified, and a nucleotide sequence was designed to enable expression of a light chain variable region whose framework region contained a human antibody sequence. This was then inserted into a mammalian expression vector containing the light chain constant region of human IgG1. The above two recombinant expression vectors were transfected into mammalian cells according to standard methods to obtain a culture supernatant containing humanized monoclonal antibody #1 against CAPRIN-1 (humanized antibody #1).

[0149] The culture supernatant containing the obtained humanized anti-CAPRIN-1 monoclonal antibody #1 was purified using Hitrap Protein A Sepharose FF (GE Healthcare) according to standard methods, replaced with PBS(-), and filtered through a 0.22 μm filter (Millipore) to prepare a sample.

[0150] The specific reactivity of the above anti-CAPRIN-1 antibody to the CAPRIN-1 protein was confirmed by immobilizing the CAPRIN-1 protein on a plate and detecting it using ELISA.

[0151] Furthermore, by using the above anti-CAPRIN-1 antibody and flow cytometry to examine its reactivity with cancer cells whose cell membranes had not been permeabilized, it was confirmed that a portion of CAPRIN-1 was expressed on the cell membrane surface of cancer cells, as shown in the examples below.

[0152] Flow cytometry has confirmed the expression of CAPRIN-1 gene in the following human cancer cells: breast cancer cells (BT-474), colon cancer cells (HT-29), lung cancer cells (QG56, H1650), gastric cancer cells (NCI-N87), uterine cancer cells (HEC-1-A), prostate cancer cells (22Rv1), pancreatic cancer cells (Panc10.5), liver cancer cells (Hep3B), ovarian cancer cells (SKOV3), renal cancer cells (Caki-2), brain cancer cells (U-87MG), bladder cancer cells (T24), esophageal cancer cells (OE33), and leukemia cell lines (OCI-AML5). Humanized antibody #1 showed stronger fluorescence intensity against all cancer cells, including lymphoma cells (Ramos), gallbladder cancer cells (TGBC14TKB), fibrosarcoma cells (HT-1080), melanoma cells (G-361), mouse renal cancer cells (Renca) in which expression of the CAPRIN-1 gene has been confirmed, and mouse breast cancer cells (4T1), compared to the negative control human IgG control antibody and rabbit IgG antibody, which show no reactivity against cancer cells, and was confirmed to strongly react with the cell membrane surface of the above cancer cells in which CAPRIN-1 is expressed.

[0153] Similarly, WO2010 / 016526, WO2011 / 096517, WO2011 / 096528, WO2011 / 096519, WO2011 / 096533, WO2011 / 096534, WO2011 / 096535, WO2013 / 018886, WO2013 / 018894, WO2013 / 018892, WO2013 / 018891, W It was also confirmed that the anti-CAPRIN-1 antibodies described in WO2013 / 018889, WO2013 / 018883, WO2013 / 125636, WO2013 / 125654, WO2013 / 125640, WO2013 / 147169, WO2013 / 147176 and WO2015 / 020212 similarly react strongly with the above-mentioned cancer cell membrane surface.

[0154] Example 2: Antitumor effect of combined use of anti-CAPRIN-1 antibody and immune checkpoint inhibitor This patient with stage 4 melanoma had a history of prior immune checkpoint inhibitor therapy, including monotherapy with the anti-PD-1 antibody (nivolumab) and combination therapy with the anti-PD-1 antibody (nivolumab) and anti-CTLA-4 antibody (ipilimumab), but neither therapy was effective and the tumor continued to grow. The patient was administered a combination of the anti-PD-1 antibody (nivolumab) and a 10 mg / kg dose of TRK-950 (an anti-CAPRIN-1 antibody currently undergoing clinical trials as a cancer treatment). Computed tomography (CT) scans of metastatic tumors in the orbit, axillary lymph nodes, adrenal glands, and pelvic peritoneum revealed a 57% reduction in total tumor size approximately 40 days after the start of treatment, demonstrating a partial response. The orbital tumor had completely disappeared at the same time. A similar evaluation approximately five months after the start of treatment revealed a 65% reduction in total tumor size. Thus, it has been shown that treatment of cancer patients with a combination of anti-CAPRIN-1 antibodies and immune checkpoint inhibitors exhibits extremely strong efficacy not achieved with existing standard treatments.

[0155] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. A pharmaceutical for treating and / or preventing cancer, comprising an antibody or a fragment thereof immunologically reactive with CAPRIN-1 protein and an immune checkpoint inhibitor, either together or separately.

2. The pharmaceutical product according to claim 1, wherein the immune checkpoint inhibitor is a drug that inhibits the interaction between PD-1 and PD-L1 and / or a drug that inhibits the interaction between CTLA-4 and CD80 or CD86.

3. The pharmaceutical product according to claim 1 or 2, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, and / or an anti-CTLA-1 antibody.

4. The pharmaceutical product according to any one of claims 1 to 3, wherein the immune checkpoint inhibitor is nivolumab.

5. The pharmaceutical product according to any one of claims 1 to 4, wherein the cancer is a cancer in a cancer patient for whom cancer treatment with a pharmaceutical product other than cancer treatment with a pharmaceutical product comprising a combination, together or separately, of an antibody or a fragment thereof immunologically reactive with CAPRIN-1 protein and an immune checkpoint inhibitor has been ineffective.

6. The pharmaceutical product according to any one of claims 1 to 5, wherein the cancer is a cancer in a cancer patient for whom cancer treatment with an immune checkpoint inhibitor has not been effective.

7. The pharmaceutical product according to any one of claims 1 to 6, wherein the antibody or fragment thereof is immunologically reactive with a CAPRIN-1 protein having an amino acid sequence represented by any of the even-numbered SEQ ID NOs: 2 to 30, or an amino acid sequence having 80% or more sequence identity with said amino acid sequence.

8. The pharmaceutical product according to any one of claims 1 to 7, wherein the antibody or fragment thereof is immunologically reactive with the extracellular domain of CAPRIN-1 protein present on the surface of cancer cells.

9. The pharmaceutical product according to any one of claims 1 to 8, wherein the antibody or fragment thereof is immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having an amino acid sequence represented by any one of SEQ ID NOs: 31 to 35, 296 to 299, 308, and 309, or an amino acid sequence having 80% or more sequence identity with said amino acid sequence.

10. The pharmaceutical product according to any one of claims 1 to 9, wherein the antibody is a monoclonal antibody or a polyclonal antibody.

11. The pharmaceutical product according to any one of claims 1 to 10, wherein the antibody or fragment thereof is any one of the following (A) to (M): (A) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 36, 37, and 38, respectively, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 40, 41, and 42, respectively, and having immunological reactivity with a CAPRIN-1 protein. (B) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 44, 45, and 46, respectively, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 48, 49, and 50, respectively, and having immunological reactivity with a CAPRIN-1 protein. (C) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 52, 53, and 54, respectively, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 56, 57, and 58, respectively, and having immunological reactivity with a CAPRIN-1 protein. (D) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 60, 61, and 62, respectively, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 64, 65, and 66, respectively, and having immunological reactivity with a CAPRIN-1 protein. (E) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 170, 171, and 172, respectively, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 173, 174, and 175, respectively, and having immunological reactivity with a CAPRIN-1 protein. (F) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 176, 177, and 178, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 179, 180, and 181, respectively, and having immunological reactivity with a CAPRIN-1 protein. (G) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 182, 183 and 184, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 185, 186 and 187, respectively, and having immunological reactivity with CAPRIN-1 protein. (H) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 188, 189 and 190, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 191, 192 and 193, respectively, and having immunological reactivity with a CAPRIN-1 protein. (I) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 146, 147 and 148, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 149, 150 and 151, respectively, and having immunological reactivity with a CAPRIN-1 protein. (J) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 272, 273 and 274, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 275, 276 and 277, respectively, and having immunological reactivity with a CAPRIN-1 protein. (K) An antibody or fragment thereof having immunological reactivity with a CAPRIN-1 protein, comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 290, 291, and 292, respectively, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 293, 294, and 295, respectively. (L) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2 and CDR3, respectively) of SEQ ID NOs: 301, 302 and 303 and a light chain variable region containing the complementarity determining regions (CDR1, CDR2 and CDR3, respectively) of SEQ ID NOs: 305, 306 and 307, and having immunological reactivity with the CAPRIN-1 protein. (M) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 134, 135, and 136, respectively, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 137, 138, and 139, respectively, and having immunological reactivity with a CAPRIN-1 protein.

12. The pharmaceutical product according to any one of claims 1 to 11, wherein the antibody or fragment thereof is any one of the following (a) to (al): (a) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 39 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 43; (b) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 47 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 51; (c) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 55 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

59. (d) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 63 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

67. (e) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 68 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

69. (f) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 70 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

71. (g) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 72 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 73; (h) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 74 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

75. (i) An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 76 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

77. (j) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 78 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 79; (k) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 80 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

81. (l) An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 82 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

83. (m) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 84 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

85. (n) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 86 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 87; (O) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 88 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

89. (P) An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 90 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

91. (q) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 92 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 93; (r) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 94 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

95. (s) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 96 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

97. (T) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 98 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

99. (u) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 100 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

101. (v) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 102 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

103. (w) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 104 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

105. (x) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 106 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

107. (Y) An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 108 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

109. (z) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 110 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

111. (aa) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 112 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

113. (ab) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 114 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

115. (ac) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 116 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

117. (ad) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 118 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

119. (ae) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 120 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

121. (af) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 122 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

123. (ag) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 124 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

125. (ah) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 126 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

127. (ai) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 128 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

129. (aj) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 130 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

131. (ak) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 132 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

133. (i) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 300 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

304.

13. The pharmaceutical product according to any one of claims 1 to 12, wherein the antibody is a human antibody, a humanized antibody, a chimeric antibody, or a single-chain antibody.

14. The pharmaceutical product according to any one of claims 1 to 13, wherein the cancer is a cancer that expresses CAPRIN-1 protein on the cell membrane surface.

15. The pharmaceutical product according to any one of claims 1 to 14, wherein the cancer is melanoma, breast cancer, kidney cancer, colon cancer, pancreatic cancer, lung cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancer, gastric cancer, mesothelial carcinoma, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, hepatocellular carcinoma, glioblastoma, urothelial carcinoma, ovarian cancer, bladder cancer, uterine cancer, primary central nervous system lymphoma, primary testicular lymphoma, biliary tract cancer, bile duct cancer, brain tumor, prostate cancer, leukemia, lymphoma, liver cancer, sarcoma, fibrosarcoma, mast cell tumor, adrenocortical carcinoma, Ewing's tumor, multiple myeloma, testicular cancer, thyroid cancer, basal cell carcinoma, Paget's disease, or skin cancer.

16. An efficacy enhancer for a pharmaceutical composition for treating and / or preventing cancer, which comprises an immune checkpoint inhibitor as an active ingredient, and an antibody or a fragment thereof that is immunologically reactive with CAPRIN-1 protein as an active ingredient.

17. A pharmaceutical efficacy enhancer for a pharmaceutical composition for treating and / or preventing cancer, which comprises an immune checkpoint inhibitor as an active ingredient, and which comprises an antibody or a fragment thereof that is immunologically reactive with CAPRIN-1 protein as an active ingredient.

18. A method for treating and / or preventing cancer, comprising administering to a subject an antibody or a fragment thereof immunologically reactive with CAPRIN-1 protein and an immune checkpoint inhibitor, either together or separately.